Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM6HVO6)

• DOT Name: 3'-5' exoribonuclease HELZ2 (HELZ2)
• Synonyms: EC 3.1.13.1; ATP-dependent RNA helicase PRIC285; EC 3.6.4.13; Helicase with zinc finger 2, transcriptional coactivator; Helicase with zinc finger domain 2; PPAR-alpha-interacting complex protein 285; PPAR-gamma DNA-binding domain-interacting protein 1; PDIP1; PPAR-gamma DBD-interacting protein 1; Peroxisomal proliferator-activated receptor A-interacting complex 285 kDa protein
• Gene Name: HELZ2
• Related Disease:
  Dengue
  Hyperlipidemia
  Obesity
• UniProt ID: HELZ2_HUMAN
• EC Number: 3.1.13.1; 3.6.4.13
• Pfam ID: PF13086 ; PF13087 ; PF00773
• Sequence:
  MAPPGSTLLPNSPAATRGPSLARLCALVDLCLGCSRCTQRLNESTYVLRRVEHDCSREIL
  LARFKQATKSKVWRVVGCRPTFPRPLCYQVCHYYSPGLGCRRHRNRCTFARSREEALVWT
  FERQHNLQRLWLKAEVQGSGAQGGAGRAADAILTEFGGRFELLCSLCFRRCPPCICRVDP
  QGQCPEHGACPSLLAHVSAEGRRKQQFVVVRPRPRAGQPPAYCRFVGRGQPCWRGESRCQ
  FAHSAVEMAVWEAEQLGGLQRGDLLTPPAPDGDGRTAPLGQPPGAQLYCPACLVTCHSQE
  AFENHCASSEHAQMVAFDQALPWEHRSPPPGLSKFELCPKPDLCEYGDACTKAHSAQELQ
  EWVRRTQAVELRGQAAWQDGLVPYQERLLAEYQRSSSEVLVLAETLDGVRVTCNQPLMYQ
  AQERKTQYSWTFAVHSEEPLLHVALLKQEPGADFSLVAPGLPPGRLYARGERFRVPSSTA
  DFQVGVRVQAASFGTFEQWVVFDFGRRPVLLQKLGLQLGQGRRPGPCRNLALGHPEEMER
  WHTGNRHVVPGVERTAEQTALMAKYKGPALALEFNRSSVASGPISPTNYRQRMHQFLYEE
  EAAQQQLVAKLTLRGQVFLKTALQTPALNMLFAPPGALYAEVPVPSSLMPDTDQGFLLGR
  AVSTALVAPVPAPDNTVFEVRLERRASSEQALWLLLPARCCLALGLQPEARLVLEVQFQI
  DPMTFRLWHQAVDTLPEEQLVVPDLPTCALPRPWSVPPLRRGNRKQELAVALIAGWGPGD
  GRRVPPLLIYGPFGTGKTYTLAMASLEVIRRPETKVLICTHTNSAADIYIREYFHSHVSG
  GHPEATPLRVMYTDRPLSQTDPVTLQYCCLTDDRQAFRPPTRAELARHRVVVTTTSQARE
  LRVPVGFFSHILIDEAAQMLECEALTPLAYASHGTRLVLAGDHMQVTPRLFSVARARAAE
  HTLLHRLFLCYQQETHEVARQSRLVFHENYRCTDAIVSFISRHFYVAKGNPIHARGKVPP
  HPRHYPLMFCHVAGSPDRDMSMASWLNLAEIAQVVEKVQEAYNTWPSCWGGREQRCICVV
  SHGAQVSALRQELRRRDLGQVSVGSFEILPGRQFRVVVLSTVHTCQSLLSPGALAPEFFT
  DARVLNTVLTRAQSQLVVVGDAVALCSFGACGKLWESFIRECVERHSVCPEGLSMEQVEQ
  GVAQRRRWPPRGTQAGAAGNWEAAPEPVGDLAEEQAAVVTAMVKAEPGDEALSPASRDIT
  ATTAQTEAAAAPAGDAVKEDVVPGACAAGAAAAAGVESTEAEDAEADFWPWDGELNADDA
  ILRELLDESQKVMVTVGEDGLLDTVARPESLQQARLYENLPPAALRKLLHAEPERYRHCS
  FVPETFERASAIPLDDASSGPIQVRGRLDCGMAFAGDEVLVQLLSGDKAPEGRLRGRVLG
  VLKRKRHELAFVCRMDTWDPRIMVPINGSVTKIFVAELKDPSQVPIYSLRKGRLQRVGLE
  RLTAEARHSRLFWVQIVLWRQGFYYPLGIVREVLPEASTWEQGLRILGLEYSLRVPPSDQ
  ATITKVLQKYHTELGRVAGRREDCRAFLTFTVDPQGACNLDDALSVRDLGPRCEVAVHIT
  DVASFVPRDGVLDVEARRQGAAFYAPGREPVPMLPASLCQDVLSLLPGRDRLAISLFLTM
  EKASGQLKSLRFAPSVVQSDRQLSYEEAEEVIRQHPGAGRELPARLDSVDACVVAACYFS
  RLLRRHRLRSDCFYEQPDEDGTLGFRAAHIMVKEYMIQFNRLVAEFLVGSECTRTVTPLR
  WQPAPRSQQLKALCEKHGDRVPLSLHLGHHLHGGGGSPPDTRLHLLASLWKQVQFAARTQ
  DYEQMVDLVTTDDMHPFLAPAGRDLRKALERSAFGRCARGHQQQGGHYSLQVDWYTWATS
  PIRRYLDVVLQRQILLALGHGGSAYSARDIDGLCQAFSLQHALAQSYQRRARSLHLAVQL
  KAQPLDKLGFVVDVEAGSRCFRLLFPSNRETLPDPCPVPYGSLQLAEHPHALAGRPGLRL
  LWRRRVYSAQGSSPPLPLPGTVPDPHTLAVETALWKQLLELVELQRWPEAAALIQEKGEA
  SQRRELVQVQRSHCGHFLEVARELGSGDTLQVQLGTSLQHGFLVPSPQLWTVAPGFSLCL
  EHVERPGDCFSGRVYRAPRDRYRDVDEYACVWEPFCALESATGAVAENDSVTLQHLSVSW
  EASRTPQGQLQGAFRLEAAFLEENCADINFSCCYLCIRLEGLPAPTASPRPGPSSLGPGL
  NVDPGTYTWVAHGQTQDWDQERRADRQEAPRRVHLFVHHMGMEKVPEEVLRPGTLFTVEL
  LPKQLPDLRKEEAVRGLEEASPLVTSIALGRPVPQPLCRVIPSRFLERQTYNIPGGRHKL
  NPSQNVAVREALEKPFTVIQGPPGTGKTIVGLHIVFWFHKSNQEQVQPGGPPRGEKRLGG
  PCILYCGPSNKSVDVLAGLLLRRMELKPLRVYSEQAEASEFPVPRVGSRKLLRKSPREGR
  PNQSLRSITLHHRIRQAPNPYSSEIKAFDTRLQRGELFSREDLVWYKKVLWEARKFELDR
  HEVILCTCSCAASASLKILDVRQILVDEAGMATEPETLIPLVQFPQAEKVVLLGDHKQLR
  PVVKNERLQNLGLDRSLFERYHEDAHMLDTQYRMHEGICAFPSVAFYKSKLKTWQGLRRP
  PSVLGHAGKESCPVIFGHVQGHERSLLVSTDEGNENSKANLEEVAEVVRITKQLTLGRTV
  EPQDIAVLTPYNAQASEISKALRREGIAGVAVSSITKSQGSEWRYVLVSTVRTCAKSDLD
  QRPTKSWLKKFLGFVVDPNQVNVAVTRAQEGLCLIGDHLLLRCCPLWRSLLDFCEAQQTL
  VPAGQVRVCRRPTMPS
• Function: Can degrade highly structured RNAs through its concerted ATP-dependent RNA helicase and 3' to 5' exoribonuclease activities. Shows a strong preference for pyrimidine over purine residues for its nuclease activity. Acts as a transcriptional coactivator for a number of nuclear receptors including PPARA, PPARG, THRA, THRB and RXRA.
• Tissue Specificity: Expressed in various tissues including heart, pancreas, skeletal muscle, colon, spleen, liver, kidney, lung, peripheral blood and placenta.
• Reactome Pathway:
  BMAL1 (R-HSA-1368108)
  PPARA activates gene expression (R-HSA-1989781)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Regulation of lipid metabolism by PPARalpha (R-HSA-400206)
  Circadian Clock (R-HSA-400253)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  Heme signaling (R-HSA-9707616)
  RORA activates gene expression (R-HSA-1368082)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dengue	DISKH221	Strong	Biomarker	[1]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Biomarker	[2]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of 3'-5' exoribonuclease HELZ2 (HELZ2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of 3'-5' exoribonuclease HELZ2 (HELZ2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 3'-5' exoribonuclease HELZ2 (HELZ2).	[14]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of 3'-5' exoribonuclease HELZ2 (HELZ2).	[8]

References

• [1] HELZ2 Is an IFN Effector Mediating Suppression of Dengue Virus.Front Microbiol. 2017 Feb 20;8:240. doi: 10.3389/fmicb.2017.00240. eCollection 2017.
• [2] Protection against high-fat diet-induced obesity in Helz2-deficient male mice due to enhanced expression of hepatic leptin receptor.Endocrinology. 2014 Sep;155(9):3459-72. doi: 10.1210/en.2013-2160. Epub 2014 Jul 8.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.